Calcineurin A{beta} regulates NADPH oxidase expression and activity via NFAT in response to high glucose [Cell Biology]

December 26th, 2013 by Williams, C. R., Gooch, J. L.

Hypertrophy is an adaptive response that enables organs to appropriately meet increased functional demands. Previously, we reported that calcineurin (Cn) is required for glomerular and whole kidney hypertrophy in diabetic rodents (1,2). Since studies have also implicated the reactive oxygen species (ROS) generating-enzymes NADPH oxidases (Nox) in diabetic kidney responses, we tested the hypothesis that Nox and Cn cooperate in a common signaling pathway. First, we examined the role of the two main isoforms of Cn in hypertrophic signaling. Using primary kidney cells lacking a catalytic subunit of Cn (CnAα-/- or CnAβ-/-), we found that high glucose selectively activates CnAβ while CnAα is constitutively active. Furthermore, CnAβ but not CnAα mediates hypertrophy. Next, we found that chronic ROS generation in response to high glucose is attenuated in CnAβ-/- cells, suggesting that Cn is upstream of Nox. Consistent with this, loss of CnAβ reduces basal expression and blocks high glucose induction of Nox2 and Nox4. Inhibition of NFAT, a CnAβ-regulated transcription factor, decreases Nox2 and Nox4 expression while NFAT over-expression increases Nox2 and Nox4 indicating that the CnAβ/NFAT pathway modulates Nox. These data reveal that the CnAβ/NFAT pathway regulates Nox and plays an important role in high glucose-mediated hypertrophic responses in the kidney.